Garnett Group | Translational Cancer Genomics

Garnett Group | Translational Cancer Genomics

Garnett Group

Our Research and Approach

We investigate how abnormalities in the DNA of cells contribute to cancer and impact on patient responses to therapy. This provides fundamental insights into disease mechanisms with implications for the development of improved therapies.

There are currently four complementary research focuses in my laboratory:

The genomics of drug sensitivity. High-throughput drug screens in human cancer cell cultures to identify genetic features of cancer cells that are predictive of drug sensitivity.

Background

Cancer is a genetic disease caused by the accumulation of changes within the DNA of cells that confers a growth and survival advantage. Cancer is not just one disease, but many different diseases, each with a different spectrum of underlying genetic causes. The functional consequence of these genetic changes in the genes of healthy and cancer cells is often poorly understood, and how they contribute to disease is often unclear. Furthermore, these genetic changes can impact on patient responses to therapy and consequently can be used to select patients most likely to benefit from a specific treatment.

The Translational Cancer Genomics team investigates how genetic alterations in cancer contribute to disease and impact on response to therapy. Our research is at the interface of cancer genomics, cell biology and cancer therapeutics and employs high-throughput biology approaches together with detailed mechanistic studies.

The team have state-of-the-art facilities to perform their research including extensive robotics, acoustic dispensing, high-content microscopy, RNAi and chemical libraries, and access to core Sanger IT and genomics infrastructure.

The genomics of drug sensitivity

Heatmap of IC50s of 83 Compounds against a Panel of Colon Cancer Organoids

The team uses high-throughput drug sensitivity screens in highly annotated human cancer cell cultures to identify genetic features of cancer cells that are predictive of drug response.

The collection of cancer cell models to study drug response includes >1000 human cancer cell lines, organoids, and engineered mouse and human cells. Cell culture models are highly annotated at the level of the genome (DNA sequencing), transcriptome (gene expression and RNAseq), and epigenome (DNA methylation). The team perform single-drug and combination screens with hundreds of anti-cancer compounds across their large collection of cell culture models to detect drug sensitivity in specific tissue and genetic sub-types.

The results from these screens are used to improve the design of clinical trials through the identification of patient populations most likely to respond to a therapy.

Mapping synthetic-lethal dependencies in cancer cells

The complexity and diversity of cancer genomes represents a significant challenge when developing new cancer therapies. Specifically, identifying cellular signalling nodes and processes whose perturbation selectively kills cancer cells while sparing normal cells remains acutely difficult. This is because our understanding of which proteins are necessary for cancer cell survival is incomplete. Furthermore, our understanding of cellular networks and processes is relatively poor in normal cells, let alone in the context of cancer cells with their myriad of molecular alterations. Thus, systematic and unbiased approaches to identify critical dependencies in cancer cells could significantly expand the repertoire of new drug targets for future development.

Genome-editing technologies such as CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats) are a powerful tool for studying gene function in normal and diseased cells. This approach uses a single guide RNA (sgRNA ) to recruit the Cas9 endonuclease to a desired genomic loci to create double strand breaks, which are repaired through an error prone process resulting in targeted gene inactivation. Taking advantage of the programmable nature of the sgRNA, it is now possible to use a library of sgRNAs to perform genome-wide functional genetic screens across a diverse array of cellular models and systems.

Mathew's group, in collaboration with the laboratory of Kosuke Yusa, are exploiting CRISPR-Cas9 genome-editing technology to systematically identify new drug targets using genome-wide ‘synthetic lethal’ screens in cancer cell lines. The identification of acute sensitivities, which occurs within specific molecular/genetic sub-types, could provide novel opportunities for genetically targeted therapeutic intervention.

A new generation of organoid cancer models

Approximately 1,000 human cancer cell lines are available to scientists worldwide and this has been a useful resource for cancer research. However as we enter the era of precision medicine, poor representation of some cancer types, insufficient numbers to capture the genetic diversity of cancer, lack of clinical outcome data and lack of comparison to normal reference sample limit their use.

Novel cell culturing methods such as organoid derivation have revolutionised our ability to derive cell line models from both healthy and diseased tissue, and have the potential to overcome these limitations.

We are generating and characterising new cancer cell line models from different tumour types as experimental tools. These cell lines are being characterised at the level of the genome and transcriptome, profiled for differential sensitivity to anti-cancer therapies, and will ultimately be made available to the research community.

We anticipate that this highly annotated resource will have broad applications and serve to catalyse a new wave of discovery in fundamental cancer biology and therapeutics.

Precision organoid models to study cancer gene function

Mathew laboratory are also uses genome-editing approaches to introduce specific alterations (so called 'cancer genes') into normal and cancer cells to study their function.

These studies provide a better understanding of how cancer genes impinge on cellular processes and ultimately contribute to carcinogenesis, as well as providing insights into how specific genetic changes impact on drug response, with implications for the development of cancer therapies.

Key Projects, Collaborations, Tools & Data

The Cancer Dependency Map integrates the work of multiple experimental and computational research project at the Sanger Institute with the shared aim of identifying dependencies in cancer cells which could be exploited to develop new therapies. This knowledge is foundational for our understanding of cancer biology and the development of precision cancer medicine.

Throughout life, the genome within cells of the human body is exposed to DNA damage and suffers mistakes in replication. These corrosive influences result in progressive, subtle divergence of the DNA sequence in each cell from that originally constituted in the fertilised egg. The Cancer Genome Project uses high-throughput genome sequencing to identify these somatically acquired mutations with the aim of characterising cancer genes, mutational processes and patterns of clonal evolution in human tumours.

The Cellular Generation and Phenotyping (CGaP) core facility provides central cell biology support to the Sanger Institute, in particular the scale-up of existing protocols to facilitate 'Science at Scale'. CGaP takes a unique approach at the institute by partnering with faculty groups in order to deliver large scale projects. We function as a contract research group for the insitute, running multiple, distinct cell biology based projects. The facility has expertise in cell derivation from primary tissue, iPSC and organoid derivation, cellular differentiation, CRISPR library screens, phenotypic assays and end point analysis (e.g. Immunocytochemistry) and functional bioassays.

If you are interested in obtaining a degree level apprenticeship in the field of Cell Biology then CGaP are offering this opportunity for 1 successful candidate in 2019. The application process will open on the 1st February via https://www.findapprenticeship.service.gov.uk/apprenticeshipsearch

The Cellular Generation and Phenotyping (CGaP) core facility provides central cell biology support to the Sanger Institute, in particular the scale-up of existing protocols to facilitate 'Science at Scale'. CGaP takes a unique approach at the institute by partnering with faculty groups in order to deliver large scale projects. We function as a contract research group for the insitute, running multiple, distinct cell biology based projects. The facility has expertise in cell derivation from primary tissue, iPSC and organoid derivation, cellular differentiation, CRISPR library screens, phenotypic assays and end point analysis (e.g. Immunocytochemistry) and functional bioassays.

If you are interested in obtaining a degree level apprenticeship in the field of Cell Biology then CGaP are offering this opportunity for 1 successful candidate in 2019. The application process will open on the 1st February via https://www.findapprenticeship.service.gov.uk/apprenticeshipsearch

We measure, model, and modulate cell state. We use genome engineering and synthetic biology to create cell lines that can be employed for CRISPR/Cas9-based genetic screening and high throughput cell biology assays. We develop probabilistic models as well as software tools to accurately analyse the readouts.